Following her appearance in an episode of Apple's Way, Bertinelli was approached by producer Norman Lear to audition for the role of cooperative daughter Barbara Cooper in a new sitcom called One Day at a Time. The show debuted in late 1975 when Bertinelli was 15 years old. She appeared in 208 out of the 209 episodes before the show left the air on May 28, 1984.

In the 2005 One Day at a Time Reunion Special, Bertinelli was reunited with fellow cast members Bonnie Franklin, Mackenzie Phillips and Pat Harrington, Jr. to watch memorable clips from the original show's nine seasons. They talked about actors who had left the show as well as Phillips' drug problem, which had wreaked havoc on the set and caused Phillips to be fired from the show.

After the run of One Day at a Time, Bertinelli starred in several made-for-TV movies and miniseries, as well as making many guest appearances on various television shows.

Since 2015, Bertinelli has hosted her own show, Valerie's Home Cooking, on the Food Network. She also co-hosts the hit show Kids Baking Championship with cake artist Duff Goldman on the same channel. The show follows young children as they bake pastries and other desserts, and is currently in its third season.

Bertinelli, who has struggled with her weight, lost a total of 50 lb (23 kg) as of March 2009, and became a spokesperson for the Jenny Craig weight-loss program.[8] She appeared in several Jenny Craig commercials. Although Bertinelli is compensated for her Jenny Craig appearances, she considers herself a health and weight-loss activist rather than a hired weight-loss spokesperson. In 2008 she released the autobiography, Losing It: And Gaining My Life Back One Pound at a Time[9], which culminates in a description of her Jenny Craig experience. In 2009 she wrote a follow-up book Finding It: And Satisfying My Hunger for Life Without Opening the Fridge.[10]

Bertinelli married Eddie Van Halen on April 11, 1981. They have a son, Wolfgang (born March 16, 1991).[12] They separated in 2001 and divorced on Dec. 20, 2007.[13] In her autobiography, Bertinelli indicated the main reasons for her divorce were her husband's cocaine addiction and his refusal to quit smoking despite being diagnosed with oral cancer and losing one-third of his tongue in the treatment process.[3]

In May 2010, Bertinelli announced her engagement to financial planner Tom Vitale, with whom she had begun a relationship in 2004. They were married on January 1, 2011 in Malibu, California,[14] with Bertinelli in a custom-made dress by designer David Meister.[15]